Identification of fevR, a novel regulator of virulence gene expression in Francisella novicida
Identification of fevR, a novel regulator of virulence gene expression in Francisella novicida
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DOI：
10.1128/iai.00430-08
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发表时间：
2008-08-01
影响因子：
3.1
通讯作者：
Monack, Denise M.
中科院分区：
文献类型：
--
作者：
Broteke, Anna;Monack, Denise M.
土拉弗朗西斯菌感染野生动物和人类引起兔热病。这种病原体以巨噬细胞的胞浆为目标，利用弗朗西斯菌致病岛 (FPI) 中的基因进行复制。弗朗西斯菌的毒力基因调控很复杂，但转录调控因子 MglA 和 SspA 已被证明可以调控大约 100 个基因的表达，包括整个 FPI。我们利用新杀弗朗西斯菌转座子突变体库来鉴定其他调节因子，并鉴定了毒力基因表达所必需的另外五个基因。所有弗朗西斯菌属物种中都存在一种调节基因 FTN_0480（fevR，弗朗西斯菌毒力调节效应子），它是 FPI 基因和 MglA/SspA 调节子中其他基因的表达所必需的。 fevR 的表达受 MglA 正向调节。然而，mglA突变株中fevR的组成型表达并没有恢复MgIA/SspA调节子的表达，这表明mgl4和fevR并行作用以正向调节毒力基因表达。毒力研究表明，fevR 对于巨噬细胞和小鼠中的细菌复制至关重要，我们还表明，fevR 对于体内 MgIA/SspA 调节子中的基因表达是必需的。因此，fevR 是弗朗西斯菌中的一个关键毒力基因，是表达已知对于该病原体破坏宿主防御和体内发病机制所必需的毒力因子所必需的。
Francisella tularensis infects wild animals and humans to cause tularemia. This pathogen targets the cytosol of macrophages, where it replicates using the genes in the Francisella pathogenicity island (FPI). Virulence gene regulation in Francisella is complex, but transcriptional regulators MglA and SspA have been shown to regulate the expression of approximately 100 genes, including the entire FPI. We utilized a Francisella novicida transposon mutant library to identify additional regulatory factors and identified five additional genes that are essential for virulence gene expression. One regulatory gene, FTN_0480 (fevR, Francisella effector of virulence regulation), present in all Francisella species, is required for expression of the FPI genes and other genes in the MglA/SspA regulon. The expression of fevR is positively regulated by MglA. However, constitutive expression of fevR in an mglA mutant strain did not restore expression of the MgIA/SspA regulon, demonstrating that mgl4 and fevR act in parallel to positively regulate virulence gene expression. Virulence studies revealed that fevR is essential for bacterial replication in macrophages and in mice, where we additionally show that fevR is required for the expression of genes in the MgIA/SspA regulon in vivo. Thus, fevR is a crucial virulence gene in Francisella, required for the expression of virulence factors known to be essential for this pathogen's subversion of host defenses and pathogenesis in vivo.